Institute of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France.
Université de Paris, BFA, UMR 8251, CNRS, F-75014, Paris, France.
Environ Pollut. 2021 Jun 1;278:116755. doi: 10.1016/j.envpol.2021.116755. Epub 2021 Feb 22.
Epidemiological indications connect maternal and developmental presence or exposure to pesticides with an increased risk for a spectrum of neurological trajectories. To provide pre-clinical data in support of this hypothesis, we used two distinct experimental models. First, female and male mice were fed immediately prior to mating, and the resulting pregnant dams were continously fed during gestation and lactation periods using chow pellets containing a cocktail of six pesticides at tolerable daily intake levels. Male and female offspring were then tracked for behavioral and in vivo electrophysiological adaptations. Second, a zebrafish model allowed us to screen toxicity and motor-behavior outcomes specifically associated with the developmental exposure to a low-to-high concentration range of the cocktail and of each individual pesticide. Here, we report anxiety-like behavior in aging male mice maternally exposed to the cocktail, as compared to age and gender matched sham animals. In parallel, in vivo electrocorticography revealed a decrease in gamma (40-80 Hz) and an increase of theta (6-9 Hz) waves, delineating a long-term, age-dependent, neuronal slowing. Neurological changes were not accompanied by brain structural malformations. Next, by using zebrafish larvae, we showed an increase of all motor-behavioral parameters resulting from the developmental exposure to 10 μg/L of pesticide cocktail, an outcome that was not associated with midbrain structural or neurovascular modifications as assessed by in vivo 2-photon microscopy. When screening each pesticide, chlorpyrifos elicited modifications of swimming parameters at 0.1 μg/L, while other components provoked changes from 0.5 μg/L. Ziram was the single most toxic component inducing developmental malformations and mortality at 10 μg/L. Although we have employed non-equivalent modalities and timing of exposure in two dissimilar experimental models, these outcomes indicate that presence of a pesticide cocktail during perinatal periods represents an element promoting behavioral and neurophysiological modifications. The study limitations and the possible pertinence of our findings to ecotoxicology and public health are critically discussed.
流行病学迹象表明，母体和发育过程中接触或暴露于农药会增加一系列神经发育轨迹的风险。为了提供支持这一假设的临床前数据，我们使用了两种不同的实验模型。首先，雌性和雄性小鼠在交配前立即喂食，然后在妊娠和哺乳期期间，用含有六种农药混合物的标准食物持续喂养受孕的母鼠，该混合物的浓度处于可耐受日摄入量水平。然后，对雄性和雌性后代的行为和体内电生理适应性进行跟踪。其次，斑马鱼模型使我们能够筛选与鸡尾酒和每种农药的低至高浓度范围发育暴露相关的毒性和运动行为结果。在这里，我们报告了母体接触鸡尾酒的雄性老年小鼠的焦虑样行为，与年龄和性别匹配的假手术动物相比。与此同时，体内皮层电图显示，γ（40-80Hz）波减少，θ（6-9Hz）波增加，表明存在长期、年龄依赖性的神经元活动减慢。神经变化没有伴随大脑结构畸形。接下来，通过使用斑马鱼幼虫，我们发现发育暴露于 10μg/L 农药混合物会导致所有运动行为参数增加，这种结果与通过体内 2 光子显微镜评估的中脑结构或神经血管改变无关。当筛选每种农药时，氯蜱硫磷在 0.1μg/L 时引起游泳参数的改变，而其他成分在 0.5μg/L 时引起变化。乙撑硫脲是唯一一种在 10μg/L 时引起发育畸形和死亡率的毒性成分。尽管我们在两种不同的实验模型中使用了非等效的暴露方式和时间，但这些结果表明，围产期存在农药混合物是促进行为和神经生理改变的一个因素。研究的局限性以及我们的发现对生态毒理学和公共卫生的可能相关性被批判性地讨论。
